Melanoma tumors are characterized by their aggressiveness as well as by their resistance to therapeutic treatments. In the last years, major breakthroughs have been achieved in melanoma treatment as exemplified by the successful development and use of BRAF mutant inhibitors, a mutation that occurs in approximately 50% of human melanomas. However, the high degree of heterogeneity of melanoma tumors allows them to rapidly develop resistant mechanisms after clinical treatment. Thus, there are fundamental questions in melanoma biology that need to be addressed. Among them are the metabolic vulnerabilities and mechanisms of metastasis that will be investigated in this grant. Cancer cells use metabolic/energetic pathways that are critical to maintain survival and promote tumor growth and metastasis, however the specific role of these pathways and the effect on tumor progression are not completely understood. We have recently identified a subset of human melanomas (8-10%) that aberrantly overexpress the transcriptional coactivator PGC1 (OXPHOS high) that induces mitochondrial and ROS detoxification genes. PGC1 maintains survival and protect these tumors against oxidative stress and ROS-inducing drugs, but are vulnerable to mitochondrial OXPHOS inhibition. However, PGC1 suppression in melanoma tumors allows metabolic/energetic compensation through HIF1-dependent glycolysis and metastatic progression. These results underscore the metabolic plasticity of melanomas and show that a rational combinatorial therapy will be required to treat tumors using metabolic targets. Here, we propose to continue our studies on the identification of mechanisms and targets by which human melanoma tumors reprogram metabolism conferring different vulnerabilities on cell growth and survival as well as the impact on metastasis. The goals are centered in three central aims: 1) defining the mechanisms and targets by which PGC1 controls melanoma tumor progression (Specific Aim 1), 2) identifying the metabolic compensatory mechanisms that allow survival in melanoma tumors via the HIF1 pathway (Specific Aim 2) and, 3) defining the impact and mechanisms of PGC1 on melanoma metastatic processes (Specific Aim 3). The outcomes of this proposal will advance our understanding of tumor melanoma and metabolic/energetic vulnerabilities and inform us on the identification of novel therapeutic targets in melanoma progression and metastasis.